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The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

ABSTRACT: Inducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell-cell contact-dependent manner, however, it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used cultured human iPSC-derived cardiac myocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart development in vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176142 | GEO | 2021/09/08

REPOSITORIES: GEO

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Project description:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its coactivator protein Yki. The role of mammalian Tead proteins in growth regulation, however, remains unknown. Here we examined the role of mouse Tead proteins in growth regulation. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of Tead proteins by modulating nuclear localization of a Yki homologue, Yap, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition, and promotion of tumor formation. Growth promoting activities of various Yap mutants correlated with their Tead-coactivator activities. Tead2-VP16 and Yap regulated largely overlapping sets of genes. However, only a few of the Tead/Yapregulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap-/- embryos. Most of the previously identified Yap-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap and Tead1 varied depending on cell types. Strong nuclear accumulation of Yap and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap regulate cell proliferation differ depending on cell types, and Tead, Yap and Hippo signaling may play multiple roles in mouse embryos. We used microarrays to know the gene expression profiles regurated by Tead2-VP16, Tead2-EnR, Yap, and cell density in NIH3T3 cells. Keywords: Cell density, genetic modification Tead2-VP16-, Tead2-EnR-, Yap- and control vector-expressing cells were cultured at low or high density for RNA extraction and hybridization on Affymetrix microarrays.

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The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes

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